The emergence of targeted drugs in breast cancer to prevent resistance to endocrine treatment and chemotherapy.

INTRODUCTION: Deregulated signaling pathways are associated with resistance to chemotherapy and endocrine treatment, providing a rationale for the implementation of novel targeted therapies in breast cancer therapy. Key molecules targeted therapeutically in ongoing clinical breast cancer trials are phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR), Src, insulin-like growth factor 1 receptor, heat shock protein-90, histone deacetylases, cyclin-dependent kinases (CDKs), Notch and human epidermal growth factor receptors (HERs). AREAS COVERED: This review provides an overview of novel targeted agents currently explored in clinical breast cancer trials and registered in ClinicalTrials.gov. The main focus will be on their ability to prevent or reverse endocrine resistance and chemoresistance in breast cancer. EXPERT OPINION: HER2 targeted agents have extended survival substantially, both in the adjuvant and metastatic setting, pointing to a crucial dependency on this pathway in HER2-amplified breast cancer, including drug resistance reversal. While data on mTOR inhibitors are encouraging and preliminary results on CDK4/6 and Src inhibitors exciting, so far other targeted agents have been of limited benefit when added in concert with conventional therapies. Future clinical trials should systematically explore biomarkers and defects in functional gene cascades to identify relevant biological mechanisms to be targeted therapeutically in breast cancer.